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Article |
Adenovirus RID-
activates an autonomous cholesterol regulatory mechanism that rescues defects linked to Niemann-Pick disease type C
Correspondence to Cathleen R. Carlin: cathleen.carlin{at}case.edu
Host–pathogen interactions are important model systems for understanding fundamental cell biological processes. In this study, we describe a cholesterol-trafficking pathway induced by the adenovirus membrane protein RID-
that also subverts the cellular autophagy pathway during early stages of an acute infection. A palmitoylation-defective RID- mutant deregulates cholesterol homeostasis and elicits lysosomal storage abnormalities similar to mutations associated with Niemann-Pick type C (NPC) disease. Wild-type RID- rescues lipid-sorting defects in cells from patients with this disease by a mechanism involving a class III phosphatidylinositol-3-kinase. In contrast to NPC disease gene products that are localized to late endosomes/lysosomes, RID- induces the accumulation of autophagy-like vesicles with a unique molecular composition. Ectopic RID- regulates intracellular cholesterol trafficking at two distinct levels: the egress from endosomes and transport to the endoplasmic reticulum necessary for homeostatic gene regulation. However, RID- also induces a novel cellular phenotype, suggesting that it activates an autonomous cholesterol regulatory mechanism distinct from NPC disease gene products.
Abbreviations used in this paper: 2-BP, 2-bromopalmitate; 3-MA, 3-methyladenine; Ad, adenovirus; CT-B, cholera toxin subunit B; DRM, detergent-resistant membrane; EE, early endosome; EGFR, EGF receptor; HB, homogenization buffer; HC, hydroxycholesterol; HMGR, 3-hydroxy-3-methyglutaryl-CoA reductase; LBPA, lysobisphosphatidic acid; LDL, low density lipoprotein; LDLR, LDL receptor; LE, late endosome; LPDS, lipoprotein-deficient serum; LSD, lysosomal storage disease; LSO, lysosomal storage organelle; LXR, liver X receptor; MDC, monodansylcadaverine; MPR, mannose 6-phosphate receptor; MT, microtubule; MVB, multivesicular body; NPC, Niemann-Pick type C; ORP1L, oxysterol-binding protein–related protein 1L; PI3K, phosphatidylinositol-3-kinase; PM, plasma membrane; RILP, Rab7-interacting lysosomal protein; RIPA, radioimmunoprecipitation assay; SREBP, sterol regulatory element–binding protein; TfR, transferrin receptor.
© 2009 Cianciola and Carlin
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
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